Soluble interleukin-6 receptor mediated fatigue highlights immunological heterogeneity of patients with early breast cancer who undergo radiation therapy

PURPOSE: This study aimed to explore the associations between dose-volume parameters of localized breast irradiation, longitudinal interleukin-6 soluble receptor (sIL-6R), and leukocyte counts as markers of an immune-mediated response and fatigue as a centrally-driven behavior. METHODS AND MATERIALS: This prospective cohort study recruited 100 women who were diagnosed with stage 0-IIIa breast cancer, prescribed 40 Gy in 15 fractions over 3 weeks adjuvant radiation therapy, and had no prior or concurrent chemotherapy. Dose-volume parameters were derived from treatment plans and related to serum sIL-6R concentrations, leukocyte counts, and a validated measure of self-reported fatigue at baseline, after 10 and 15 fractions, and 4 weeks after radiation therapy. RESULTS: sIL-6R concertation was significantly higher in patients with a total volume of tissue irradiated within the 50% isodose >2040 cm(3) (P = .003). When controlling for body mass index, this result only remained significant after treatment. The volume of liver irradiated within the 10% isodose correlated with the sIL-6R concentration during and after radiation therapy (ρ = .3-.4; P = .03-.007). The 38% of the cohort that was classified as fatigued had a higher mean sIL-6sR concentration at all observation points, but the differences were only statistically significant during radiation therapy: Mean (standard deviation [SD]) after 15 fractions for fatigued patients was 47.6 ng/dL (11.2 SD) versus 41.6 ng/dL (11.4 SD) for nonfatigued patients (P = .01). Cohort leukocyte counts and leukocyte subsets decreased consistently from baseline and the values for the fatigued group were 4% lower at baseline and between 7% and 9% lower during and after treatment compared with those of the nonfatigued group but the differences were not statistically significant. CONCLUSIONS: This is the first study to show that localized irradiation induces increased systemic sIL-6R during treatment in participants who reported elevated levels of fatigue before, during, and after treatment. This behavioral response appears to reflect a variation in innate host immunity, which then mediates the cellular and/or psychological stress of radiation therapy.